No / The naturally occurring bitter principle quassin (1) was converted chemically into the gamma-lactone quassilactone (13) in an attempt to enhance its antiplasmodial activity. The in vitro antiplasmodial activity of 13 against Plasmodium falciparum (K1) (IC(50) = 23 microM) was 40-fold greater than that of 1. However, one of the intermediates, compound 8, the 15beta-hydroxy,16-O-m-chlorobenzoyl analogue of 1, was 506-fold more active than 1 against P. falciparum (IC(50) = 1.8 microM) and only 3-fold less potent than chloroquine. In addition, 8 displayed the best cytotoxic/antiplasmodial ratio (112) of all of the compounds tested. In the course of this work a dimer, neoquassin ether (6), linked at C-16 was also prepared; 6 was found to have weak antiplasmodial activity (IC(50) = 9.7 microM).

L'objectif de ce travail consiste en la synthèse et l'évaluation antiparasitaire in vitro de nouveaux dérivés du thiazole et apparentés. Plusieurs stratégies de synthèse visant à une pharmacomodulation en séries mono- et polycycliques ont été étudiées : en série 2-méthyl-5-nitrothiazole, la pharmacomodulation anti-Trichomonas de la position 4 par stratégie SRN1 n'a pas permis d'améliorer l'activité déjà démontrée en série 2-méthyl-5-nitroimidazole, mais a conduit à des dérivés à activité antiproliférative in vitro, spécifique de la lignée HepG2. En série 4-arylsulfonylméthyl-2-méthylthiazole, la pharmacomodulation de la position 5, par couplage de Suzuki-Miyaura d'une part, et par arylation directe et réaction de Knoevenagel intramoléculaire d'autre part, a conduit à des dérivés mono- et polycycliques dont certains ont démontré une activité antiplasmodiale in vitro encourageante. En série 5H-thiazolo[3,2-a]pyrimidin-5-one, la réaction de double couplage de Suzuki-Miyaura a révélé l'importance du groupement phényle en position 6 pour l'activité antiplasmodiale de ces dérivés. Enfin, l'évaluation biologique in vitro de thiéno[3,2-d]pyrimidin-4(3H)-ones a permis de caractériser le pharmacophore responsable de l'activité antiplasmodiale significative de cette série. Les résultats préliminaires encourageants d'une étude mécanistique antiplasmodiale présentent l'inhibition spécifique des kinases plasmodiales comme un mécanisme d'action potentiel de ces composés. / The objective of this work consists of the synthesis and the antiparasitic in vitro evaluation of new thiazole derivatives and related structures. Several synthetic strategies aiming at the pharmacomodulation on mono- and polycyclic series have been studied: in 2-methyl-5-nitrothiazole series, the anti-Trichomonas pharmacomodulation on position 4 by SRN1 strategy did not improve the activity previously demonstrated in 2-methyl-5-nitroimidazole series, but led to derivatives displaying a selective in vitro antiproliferative activity toward the HepG2 cell line. In 4-arylsulfonylmethyl-2-methylthiazole series, the pharmacomodulation on position 5, by Suzuki-Miyaura cross-coupling reaction on the one hand, and by direct arylation and intramolecular Knoevenagel reaction on the other hand, led to mono- and polycyclic derivatives among which some displayed an encouraging in vitro antiplasmodial activity. In 5H-thiazolo[3,2-a]pyrimidin-5-one series, a double Suzuki-Miyaura cross-coupling reaction revealed that the phenyl group on position 6 contributes to the antiplasmodial effect of this series. Finally, the in vitro biological evaluation of the thieno[3,2-d]pyrimidin-4(3H)-one scaffold let to characterize the pharmacophore responsible for the significant antiplasmodial activity. Some preliminary encouraging results regarding a mechanistic antiplasmodial study show the specific inhibition of plasmodial kinases, as a potential mechanism of action of some of these compounds.